Clinical issue

Liver disease results from intrinsic causes, such as mitochondrial defects or cancer, or from exposure to external agents such as chemicals, toxins or viruses. Although a damaged liver can regenerate, acute liver damage and failure is normally treated by organ transplantation, which is hampered by a severe shortage of suitable donors and, even when successful, reduces patient life span significantly. To help improve transplant procedures, and ultimately to provide a source of healthy hepatic tissue, the process by which the liver regenerates, and how this process can be enhanced, needs to be better understood.

Results

This paper describes a zebrafish model for liver regeneration. The authors used a forward genetic screen in which they chemically mutagenized zebrafish adult males and then looked for liver defects in their F3 progeny – this screen led to the identification of a mutant they called oliver. oliver mutants have an o-shaped liver (o-liver) of much reduced size owing to the depletion of most of the hepatocytes. oliver maps to the tomm22 gene, which encodes a translocase of the outer mitochondrial membrane, thought to play an important role in protein import into mitochondria. Morpholino injections, in which modified oligonucleotides (morpholinos) directed against tomm22 mRNA inhibited tomm22 translation, showed that knockdown of Tomm22 protein resulted in the same phenotype as that found in oliver mutants, thus confirming that tomm22 is required for hepatocyte survival. Importantly, as protein knockdown by morpholino only lasts until the morpholino is used up, the authors could show that when Tomm22 levels recovered, the liver mass also recovered, suggesting that liver damage caused by mitochondrial dysfunction can be reversible. Loss of the Wnt2b signaling pathway, which is required for liver development, inhibited the regeneration process in tomm22 morpholino-injected embryos, indicating some overlap in the control mechanisms between normal development and regeneration.

Implications and future directions

The ease of producing and screening large numbers of zebrafish makes the tomm22 liver regeneration assay suitable for large-scale chemical and genetic screens for molecules or genes modulating hepatocyte regeneration in the absence of most hepatocytes. tomm22 mutant fish will also be useful for identifying the lineage from which regenerating hepatocytes originate, and provide a whole-organism model for studying hepatic mitochondrial diseases.

Trichur R. Raju and colleagues explore how the pathological changes of the skeletal muscle can significantly damage motor neurons, leading to progressive neurodegeneration in amyotrophic lateral sclerosis.

The chronic pain experienced by a number of patients with diabetes has widely been assumed to originate from damage to blood vessels or to local tissue surrounding neurons caused by high blood-sugar levels. However, a new study reports that in fruit flies, this pain hypersensitivity results instead from disrupted insulin signalling in pain sensory neurons.

Currently used animal models of critical-sized bone defects and the regenerative bone tissue engineering strategies used in these models are reviewed by Jacqui Anne McGovern, Michelle Griffin and Dietmar Werner Hutmacher, as well as the application of bone tissue engineering for the advancement of cancer xenograft models.

We are currently seeking proposals for four Workshops to be held in 2020. Do you have an idea for a Workshop? Please let us know and you could be one of our 2020 Workshop organisers. You focus on the science, we focus on the logistics. We are particularly keen to receive proposals from postdocs. Deadline date for applications is 25 May 2018.

Elizabeth Rhea, a postdoctoral fellow at the University of Washington, USA, used a Travelling Fellowship from DMM to travel to Monash University in Melbourne, Australia. There, Elizabeth worked on developing a method to use the buccal mucosa as a model for screening enhancers of intranasal insulin delivery. Read more on her story here.

Where could your research take you? Join Elizabeth and apply for the next round of Travelling Fellowships from DMM by 25 May 2018.

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Meet the preLighters! In the latest interview with our preLights community, the preLights team caught up with James Gagnon, Assistant Professor at the University of Utah, to talk about his research, how science can be made more open, his enthusiasm for the preLights project and the fun sides of being a junior PI.